All of the > one million total joint replacements/year that are performed in the United States are expected to eventually fail if their recipients live log enough, due to implant debris induced inflammatory responses. This is particularly troubling for millions of elderly people who may need a revision in their last decades of life where the incidence of mortality of major surgery can be as high as 13% (vs. <1% in patients <75 years of age). Non-surgical treatments to extend implant life are currently unavailable. Debris induced inflammation is well known to induce local innate immune responses, i.e. monocytes/macrophages activate NF and secretion of IL-1, TNF, IL-6 and IL-8 resulting in localized inflammation. However, implant debris are sterile, relatively inert, and do not present the molecular patterns of a typical pathogen. So, how do extra- and intracellular mechanisms sense and respond to exogenous non-biological challenge agents such as implant debris? Recent progress points to the involvement of the inflammasome, a danger signaling pathway. Our recently published initial findings on implant debris-induced inflammasome activation provide an important insight into this pathway that can sense stress and danger signals triggered by contact with certain non-biological challenge agents, including particulate adjuvants present in modern vaccines. These results suggest that inflammasome danger signaling is central to potentiating innate macrophage-based responses to implant debris (i.e. from initial lysosomal destabilization and NADPH oxidase induction of ROS, to NALP3-ASC oligomerization, and Caspase 1 conversion of pro-IL-1 to IL-1. Our long term goal is to understand how to manipulate the inflammasome pathway to mitigate the untoward effects of implant debris. The objective of this proposal is to determine both the utility of this approach an how best to mitigate implant debris induced osteolysis. Several key questions are: 1) what component(s) of the inflammasome pathway are best targeted to reduce debris-mediated inflammation? 2) Can inhibition of debris induced inflammasome activation lead to decreased aseptic osteolysis in vivo, i.e. is it a viable target for pharmacotherapy? 3) Does debris induced inflammasome activation preferentially occur in people with debris-induced aseptic osteolysis? We propose to examine these three questions under the following central hypothesis. We hypothesize that implant debris induced inflammasome danger signaling is central to implant debris immune reactivity and blocking this response is an effective means to mitigate implant debris induced aseptic osteolysis. We plan to test our central hypothesis and accomplish the objective of this application by pursuing the following three specific aims. Specific Aim 1 is to determine, whether clinically available inflammasome-specific drugs are as effective in preventing general macrophage inflammatory responses vs. other (non-clinical) inflammasome-pathway-specific inhibitors and if lysosomal destabilization is critical for the initiation of debrs-induced inflammasome activation. Specific Aim 2 is to determine the effect of blocking the inflammasome pathway on particle induced inflammation and aseptic wear debris-induced osteolysis using an established animal model. Specific Aim 3 is to determine the clinical relevance of treating debris-induced inflammation by blocking the inflammasome pathway. We will test the effectiveness of selective inflammasome inhibition on wear debris-induced pro-inflammatory cytokine production by primary monocyte/macrophage cultures from arthroplasty cohorts, and determine if these effects correlate with inflammasome activity in peri-implant tissues determined by quantitative immunohistochemistry and tissue cytokine expression. This translational study will determine if inflammasome danger signaling activation to implant debris is an effective new target for pharmacologically addressing aseptic osteolysis. We expect to substantially forward our understanding of how sterile non-biological implant debris actually induces an immune system response that leads to aseptic osteolysis. Such results will provide a positive impact and potentially powerful treatment for millions of people with implants, particularly those over 75 years of age, who may be able to block implant debris associated osteolysis, postponing indefinitely the associated morbidity and mortality of revision total joint replacement surgery.